Advances in Systemic Therapies for Rare Head and Neck Malignancies: Spotlight on Adenoid Cystic Carcinoma, Differentiated Thyroid Cancer, and Sinonasal/Paranasal Tumors.

Rare head and neck cancers, including adenoid cystic carcinoma (ACC), differentiated thyroid cancer (DTC), and sinonasal/paranasal tumors, represent a diverse pathology with shared clinical challenges, including heterogenous biology and limited prospective evidence. Although these tumors may present commonly as locally aggressive disease, there is distant metastatic potential, underscoring the complexities of treatment selection. Precision medicine has broadened the landscape of treatment modalities for these rare tumors; nevertheless, there are persistent critical needs for more robust molecular predictors to refine risk stratification, enhance prognostic accuracy, and drive innovative targeted therapies. In ACC, multikinase inhibitors remain a central systemic therapy strategy; however, emerging options targeting MYB and NOTCH pathways, theranostics by prostate-specific membrane antigen‑directed radioligand therapy, and immunotherapy are providing novel alternatives of care for patients with these malignancies. In radioactive iodine‑refractory DTC, redifferentiation approaches using an antineoplastic agent for 4-6 weeks have restored I131 uptake in selected patients. Clinical trials and real-world experiences with BRAF, MEK, RET, and NTRK inhibitors have revealed that a subset of patients may benefit from this approach to delay long-term systemic therapy initiation. Molecular testing has enabled better classification of sinonasal tumors, in which multimodal therapeutic approaches have been the cornerstone, with newer biomarkers guiding the consideration of immunotherapy implementation among other alternatives. In these rare malignancies, patient-centered care, including timely access to expert multidisciplinary teams in high-volume centers, prioritization for clinical trial enrollment, and balancing options on the basis of molecular profiles, remains essential to advance the field.